title: A three-dimensional pharmacophore modelling of ITK inhibitors and virtual screening for novel inhibitors.
abstract: Interleukin-2-inducible T-cell kinase (ITK) is a key member of the Tec family of non-receptor tyrosine kinases, and has been found to be a novel target for a number of inflammatory and autoimmune diseases. A three-dimensional pharmacophore model has been generated for protein ITK from its known inhibitors. The best HypoGen model consisted of four pharmacophore features: one hydrogen bond acceptor, one hydrogen bond donor and two hydrophobic rings. This model showed a correlation coefficient of 0.947, a root mean square deviation of 0.914 and a configuration cost of 16.866. The model was validated using test set prediction and Fischer's test. A test set containing 204 compounds showed an r(2) of 0.745 between estimated activity and activity measured experimentally. Fisher's test gave a confidence level of 95%. The best pharmacophore model (Hypo1) was then employed for virtual screening (3D database searching), including Lipinsiki's filter, to obtain a pool of more drug-like molecules. The molecular pool thus retrieved was subjected to docking analysis with a study protein to remove any molecules showing false positive activity for ITK.
authors.affiliation: Department of Pharmaceutical Science and Drug Research, Punjabi University, Patiala, Punjab, India.
authors.forename: V
authors.initials: V
authors.lastname: Bagga
authors.forename: O
authors.initials: O
authors.lastname: Silakari
authors.forename: V S
authors.initials: VS
authors.lastname: Ghorela
authors.forename: M S
authors.initials: MS
authors.lastname: Bahia
authors.forename: G
authors.initials: G
authors.lastname: Rambabu
authors.forename: J
authors.initials: J
authors.lastname: Sarma
mesh_terms: D008956:Models, Chemical; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase